For the past nine years, the objectives of my research have been to identify the CNS sites, the central neurochemical systems, and the peripheral physiological mechanisms which regulate the cardiovascular system. Previous studies from my laboratory and others have demonstrated that electrical stimulation of specific regions in the hypothalamus controls vasomotor tone and regional vascular resistance in individual peripheral vascular beds. These results led to the hypothesis that there is a discrete arrangement of neural structures in this brain region that controls vasomotor tone in peripheral organ systems. Interpretation of these previous studies is limited since: 1) only electrical stimulation was tested 2) only regional blood flow was measured; and 3) there was no direct evaluation of effector mechanisms. To extend previous findings and address these concerns, the proposed Specific Aims will determine: 1) CNS sites; 2) CNS neurotransmitter systems; 3) CNS nerve pathways; and 4) the peripheral effector mechanisms which control specific regional and microvascular responses. These aims will be achieved by using: CNS microstimulation, microinjection, and knife cuts; autoradiography; horseradish peroxidase techniques; central and peripheral administration of pharmacological agents; pulsed Doppler analysis of regional blood flow; and intravital microscopy. Regional blood flow in the mesenteric, renal, and hindquarter circulations, and microvascular responses in skin, intestine and skeletal muscle will be compared during electrical and chemical stimulation of discrete neural sites in the hypothalamus previously implicated in the regulation of regional vascular resistance. Additional experiments will be determine neurotransmitters and other CNS sites involved. Finally, peripheral effector mechanisms will be tested by evaluating microvascular responses in tissue suffused with pharmacological blocking agents during CNS stimulation. This project relates directly to defining the role of the brain in cardiovascular homeostasis, and will add to our understanding of the interaction between the CNS and peripheral effector mechanisms which regulate regional and total peripheral resistance.